The basic goal of this proposal is to combine the power of combinatorial chemistry with the modern knowledge of cancer biology and genetics in an effort to identify novel anticancer compounds. The program project consists of one chemistry and two biology projects and two cores. The first project (Boger) proposes the production and testing of libraries targeted to protein-protein and protein-DNA interactions. The libraries produced in the past funding period will be increased to 10[6] compounds and lead optimization will continue. Project two (Cheresh) deals with the isolation of angiogenesis inhibitors. It will develop inhibitors of matrix metalloproteinase 2, refine the nanoparticle genes delivery technology of the past funding period and test inhibitors of integrin alpha3beta1. Project 3 (Vogt) proposes the isolation of small molecule regulators of the Myc network and of beta-catenin-LEF interaction. It will also continue the identification and optimization of lead anticancer compounds through cellular and in vitro assays. The cores are for animal studies and instruments. The research projects are connected and interdependent. The interactions are mutual; the reiterative process of library and compound optimization rests on the interchange of chemical materials and of biological information. The collaborating groups of this Program Project have become an integrated unit that incorporates a wide range of expertise and interests and applies them to the common goal, new anticancer compounds.